Osteoporosis is a major health concern for older women. Although all postmenopausal women are estrogen-deficient, only some develop osteoporosis; many postmenopausal women have high rates of bone turnover and bone loss. We have found that older postmenopausal women have a wide range of bone mass and rates of bone turnover and that increased turnover, as estimated by serum and urine biochemical markers, is associated with lower bone mass and greater rates of bone loss. In addition, we have shown that estrogen markedly inhibits bone resorption in this population and that the effect of estrogen to decrease activation frequency, a morphologic indicator of bone turnover in biopsy specimens, is inversely correlated with baseline levels of biochemical markers of bone resorption. We plan to test two related hypotheses regarding the role of cytokines in the pathogenesis of osteoporosis. The first is that the variability in bone turnover and bone mass seen in older estrogen-deficient women is due to differences in local cytokine production. Although several cytokines have been implicated in postmenopausal osteoporosis, we will focus on the interleukin-1 system, including interleukin-1(, interleukin-1(, interleukin-1 receptor antagonist, interleukin-1 receptor 1, and interleukin-1 receptor 2. We hypothesize that high bone turnover and low bone mass will be positively correlated with IL-1 activity in older women. The second hypothesis is that estrogen modulates local cytokine production in bone and that differences in local cytokine production in bone explain the variability in response to estrogen. We hypothesize that IL-1 activity will increase when estrogen is withdrawn from older women who are current estrogen users at baseline and that IL-1 activity will decrease when estrogen is re-introduced and that the magnitude of the changes will be correlated with changes on bone turnover and bone mass.